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Lebar, Matthew D

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Lebar

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Matthew D

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Lebar, Matthew D
Author's Publications: search.filters.isAuthorOfPublication.509bb5ec-d460-45f9-9fbb-365a93e17fc4

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    Lipoprotein Activators Stimulate Escherichia coli Penicillin-Binding Proteins by Different Mechanisms
    (American Chemical Society (ACS), 2014) Lupoli, Tania J.; Lebar, Matthew D; Markovski, Monica; Bernhardt, Thomas; Kahne, Daniel; Kahne, Suzanne
    In Escherichia coli, the bifunctional penicillin-binding proteins (PBPs), PBP1A and PBP1B, play critical roles in the final stage of peptidoglycan (PG) biosynthesis. These synthetic enzymes each possess a PG glycosyltransferase (PGT) domain and a transpeptidase (TP) domain. Recent genetic experiments have shown that PBP1A and PBP1B each require an outer membrane lipoprotein, LpoA and LpoB, respectively, to function properly in vivo. Here, we use complementary assays to show that LpoA and LpoB each increase the PGT and TP activities of their cognate PBPs, albeit by different mechanisms. LpoA directly increases the rate of the PBP1A TP reaction, which also results in enhanced PGT activity; in contrast, LpoB directly affects PGT domain activity, resulting in enhanced TP activity. These studies demonstrate bidirectional coupling of PGT and TP domain function. Additionally, the transpeptidation assay described here can be applied to study other activators or inhibitors of the TP domain of PBPs, which are validated drug targets.
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    A mutant Escherichia coli that attaches peptidoglycan to lipopolysaccharide and displays cell wall on its surface
    (eLife Sciences Publications, Ltd, 2014) Grabowicz, Marcin; Andres, Dorothee; Lebar, Matthew D; Malojčić, Goran; Kahne, Daniel; Silhavy, Thomas J
    The lipopolysaccharide (LPS) forms the surface-exposed leaflet of the outer membrane (OM) of Gram-negative bacteria, an organelle that shields the underlying peptidoglycan (PG) cell wall. Both LPS and PG are essential cell envelope components that are synthesized independently and assembled by dedicated transenvelope multiprotein complexes. We have identified a point-mutation in the gene for O-antigen ligase (WaaL) in Escherichia coli that causes LPS to be modified with PG subunits, intersecting these two pathways. Synthesis of the PG-modified LPS (LPS*) requires ready access to the small PG precursor pool but does not weaken cell wall integrity, challenging models of precursor sequestration at PG assembly machinery. LPS* is efficiently transported to the cell surface without impairing OM function. Because LPS* contains the canonical vancomycin binding site, these surface-exposed molecules confer increased vancomycin-resistance by functioning as molecular decoys that titrate the antibiotic away from its intracellular target. This unexpected LPS glycosylation fuses two potent pathogen-associated molecular patterns (PAMPs). DOI: http://dx.doi.org/10.7554/eLife.05334.001